EP2157090A1 - Pyrazinamidverbindung - Google Patents

Pyrazinamidverbindung Download PDF

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Publication number
EP2157090A1
EP2157090A1 EP08765775A EP08765775A EP2157090A1 EP 2157090 A1 EP2157090 A1 EP 2157090A1 EP 08765775 A EP08765775 A EP 08765775A EP 08765775 A EP08765775 A EP 08765775A EP 2157090 A1 EP2157090 A1 EP 2157090A1
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EP
European Patent Office
Prior art keywords
group
sulfanyl
carboxamide
triazol
pyrazine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08765775A
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English (en)
French (fr)
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EP2157090A4 (de
Inventor
Hiroki Umemiya
Kengo Watatani
Takanori Kawaguchi
Kenichi Kawabe
Takumi Okada
Shigetada Sasako
Noriko Saito
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Nissan Chemical Corp
Taisho Pharmaceutical Co Ltd
Original Assignee
Nissan Chemical Corp
Taisho Pharmaceutical Co Ltd
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Publication date
Application filed by Nissan Chemical Corp, Taisho Pharmaceutical Co Ltd filed Critical Nissan Chemical Corp
Publication of EP2157090A1 publication Critical patent/EP2157090A1/de
Publication of EP2157090A4 publication Critical patent/EP2157090A4/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a novel pyrazinamide compound having a glucokinase activating effect and a pharmaceutical containing the compound as an active ingredient.
  • Glucokinase belongs to the hexokinase family and catalyzes phosphorylation of glucose taken in a cell such as a pancreatic beta cell and a hepatic cell.
  • GK in the liver differs from that in pancreatic beta cells in the sequence of the N-terminal 15 amino acids due to a difference in splicing, but they are enzymatically identical.
  • GK controls insulin secretion in a glucose dependent manner; whereas, in the liver, GK controls the glycolysis system or glycogen synthesis to maintain/control the glucose level. It is therefore postulated that GK acts as a glucose sensor for maintaining homeostasis of a blood glucose level (see Non-Patent Document 1).
  • the postulation that GK acts as a biological glucose sensor is supported by findings of gene mutation in gene manipulated mice and humans. A mouse with homologousdeletion of GK died shortly after birth with elevated blood glucose; on the other hand, in a mouse with heterologousdeletion, elevated blood glucose and glucose tolerance insufficiency have been observed (see Non-Patent Document 2).
  • Non-Patent Document 3 human MODY 2 (maturity onset diabetes of the young), in which a GK gene mutation is detected, develops diabetes at a young age (see Non-Patent Document 4). In this gene mutation, low GK activity has been confirmed.
  • Non-Patent Document 5 a family having a gene mutation which accelerates GK activity has been reported (see Non-Patent Document 5). In this gene mutation, the affinity of GK for glucose is accelerated and a symptom of fasting hypoglycemia accompanying an elevation of a blood insulin level is observed. As described, GK is found to act as a glucose sensor in mammalians including humans.
  • a substance enhancing GK activity can increase glucose metabolism and glycogen synthesis in the liver, and glucose inducible insulin secretion from the pancreatic beta cell, thereby correcting elevated blood glucose. It is expected that, if elevated blood glucose is corrected, diabetic chronic complications, such as retinopathy, nephropathy, neurosis, ischemic heart disease and arteriosclerosis, can be treated and prevented, and further, diabetes-related disorders, such as obesity, hyperlipemia, hypertension and metabolic syndrome, can be treated and prevented. Therefore, a compound enhancing GK activity is expected to serve an effective therapeutic agent for diabetes.
  • GK is expressed not only in the pancreas and the liver but also in the feeding center and plays an important role in suppression of food intake by glucose (see Non-Patent Document 6). Therefore, it is considered that the GK activating substance also acts upon the feeding center to suppress food intake. GK is thus expected to serve as a therapeutic agent not only for diabetes but also for obesity.
  • the GK activating substance a certain type of propionamide compound, a certain type of picolinamide compound, a certain type of benzamide compound and a certain type of benzimidazole compound have been reported; however, no disclosure is made of a compound of the present invention (see Patent Documents 1, 2, 3 and 4).
  • pyrazinamide compounds structurally resemble have been reported; however, no disclosure is made of a compound of the present invention. Uses thereof are a schizophrenia therapeutic agent and a herbicide, respectively. These compounds differ in uses from a compound of the present invention (see Patent Documents 5 and 6).
  • An object of the present invention is to provide a compound having an excellent GK activation action and useful as a pharmaceutical.
  • the present inventors have conducted intensive studies with a view toward finding a compound having a GK activation action. As a result, they found that a pyrazinamide compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof achieves this object. Based on the finding, the present invention was accomplished.
  • the present invention provides (I) a pyrazinamide compound represented by formula (1), a tautomer or stereo isomer of the compound or a pharmaceutically acceptable salt thereof or a solvate thereof
  • R 1 represents a hydrogen atom, a C 1-8 alkyl group, a C 3-8 cycloalkyl group (the C 3-8 cycloalkyl group is unsubstituted or substituted with one hydroxy group), a C 2-9 heterocyclyl group (the C 2-9 heterocyclyl group is unsubstituted or substituted with one to three groups which may be the same or different and selected from the group consisting of a C 1-6 alkyl group and an oxo group), a phenyl group (the phenyl group is unsubstituted or substituted with one to three groups which may be the same or different and selected from the group consisting of a halogen atom, a hydroxy group, a trifluoromethyl group, a C
  • R 1 represents a hydrogen atom, a C 1-8 alkyl group, a C 3-8 cycloalkyl group, a C 2-9 heterocyclyl group (the C 2-9 heterocyclyl group is unsubstituted or substituted with one C 1-6 alkyl group), a phenyl group (the phenyl group is unsubstituted or substituted with one or two groups which may be the same or different and selected from the group consisting of a halogen atom, a hydroxy group, a trifluoromethyl group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group and a C 1-6 alkylsulfonyl group), a C 1
  • R 1 represents a C 1-8 alkyl group, a C 3-8 cycloalkyl group, a C 2-9 heterocyclyl group (then C 2-9 heterocyclyl group is unsubstituted or substituted with one C 1-6 alkyl group), a phenyl group (the phenyl group is unsubstituted or substituted with one or two groups which may be the same or different and selected from the group consisting of a halogen atom, a hydroxy group, a trifluoromethyl group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group and a C 1-6 alkylsulfonyl group), a C 1-9 heteroaryl group (
  • Another aspect of the present invention provides the pyrazinamide compound, a tautomer or stereo isomer of the compound or a pharmaceutically acceptable salt thereof or a solvate thereof according to (II), wherein R 2 is a C 1-9 heteroaryl group (the C 1-9 heteroaryl group is unsubstituted or substituted with one group selected from the group consisting of a hydroxy group, an amino group and a C 1-6 alkyl group), and Z is -S- in the formula (1).
  • R 2 is a C 1-9 heteroaryl group (the C 1-9 heteroaryl group is unsubstituted or substituted with one group selected from the group consisting of a hydroxy group, an amino group and a C 1-6 alkyl group), and Z is -S- in the formula (1).
  • Another aspect of the present invention provides the pyrazinamide compound, a tautomer or stereo isomer of the compound or a pharmaceutically acceptable salt thereof or a solvate thereof according to (III), wherein R 2 is a 1,6-dihydropyridazinyl group (the 1,6-dihydropyridazinyl group is substituted with one oxo group), and Z is -CH 2 - in the formula (1).
  • R 1 is a C 1-8 alkyl group, a C 3-8 cycloalkyl group, a C 2-9 heterocyclyl group, a phenyl group (the phenyl group is unsubstituted or substituted with one or two groups which may be the same or different and selected from the group consisting of a halogen atom, a hydroxy group, a trifluoromethyl group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group and a C 2-6 alkylsulfonyl group), a C 1-9 heteroaryl group or a C 1-14 arylalkyl group (the C 7-14 arylalkyl group
  • R 1 is a C 1-8 alkyl group, a C 3-8 cycloalkyl group, a C 2-9 heterocyclyl group, a phenyl group (the phenyl group is unsubstituted or substituted with one or two groups which may be the same or different and selected from the group consisting of a halogen atom, a hydroxy group, a trifluoromethyl group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylthio group and a C 1-6 alkylsulfonyl group), a C 1-9 heteroaryl group (the C 1-9 heteroaryl group is unsubstituted or substituted with one C 1-6
  • Ar is a monocyclic C 1-6 heteroaryl group represented
  • a compound having an excellent GK activation action has been successfully provided by the present invention.
  • n represents normal, "i” iso, “s” secondary, “t” tertiary, “c” cyclo, “o” ortho, “m” meta and “p” para.
  • the "C 1-6 alkyl group” represents a straight or branched alkyl group having 1 to 6 carbon atoms.
  • a methyl group, an ethyl group, a n-propyl group, a n-butyl group, a n-pentyl group, a n-hexyl group, an i-propyl group, an i-butyl group, a t-butyl group, a s-butyl group, an i-pentyl group, a neopentyl group and a t-pentyl group can be mentioned.
  • a methyl group and an ethyl group are more preferable.
  • the "C 1-8 alkyl group” represents a straight or branched alkyl group having 1 to carbon atoms.
  • a methyl group, an ethyl group, a n-propyl group, a n-butyl group, a n-pentyl group, a n-hexyl group, a n-heptyl group, a n-octyl group, an i-propyl group, an i-butyl group, a t-butyl group, a s-butyl group, an i-pentyl group, a neopentyl group and a t-pentyl group can be mentioned.
  • a methyl group, an ethyl group and an i-propyl group are more preferable.
  • the "hydroxy C 1-8 alkyl group” represents a "C 1-8 alkyl group” having a hydroxy group as a substituent.
  • a hydroxymethyl group, a 2-hydroxyethyl group, a 3-hydroxy-n-propyl group, a 2-hydroxy-n-propyl group, a 4-hydroxy-n-butyl group and a 2-hydroxy-i-propyl group can be mentioned.
  • a 2-hydroxyethyl group is more preferable.
  • the "halogen atom” represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. A fluorine atom and a chlorine atom are more preferable.
  • the "C 3-8 cycloalkyl group” represents a cycloalkyl group having 3 to 8 carbon atoms.
  • a c-propyl group, a c-butyl group, a c-pentyl group, a c-hexyl group, a c-heptyl group and a c-octyl group can be mentioned.
  • a c-hexyl group is more preferable.
  • the "C 1-6 alkoxy group” represents a straight or branched alkoxy group having 1 to 6 carbon atoms.
  • a methoxy group, an ethoxy group, a n-propoxy group, an i-propoxy group, a n-butoxy group, an i-butoxy group, a s-butoxy group, a t-butoxy group, a n-pentyloxy group, an i-pentyloxy group and a n-hexyloxy group can be mentioned.
  • a methoxy group is more preferable.
  • the "C 1-6 alkoxy C 1-8 alkyl group” represents a "C 1-8 alkyl group” having a "C 1-6 alkoxy group” as a substituent.
  • a 2-methoxyethyl group, a 2-ethoxyethyl group and a 2-i-propoxy-2-methyl-n-propyl group can be mentioned.
  • a 2-methoxyethyl group is more preferable.
  • the "C 2-6 alkoxycarbonyl group” represents a carbonyl group having a straight or branched alkoxy group having 1 to 5 carbon atoms.
  • a methoxycarbonyl group, an ethoxycarbonyl group and an i-propoxycarbonyl group can be mentioned.
  • a methoxycarbonyl group is more preferable.
  • the "C 1-6 alkylthio group” represents a straight or branched alkylthio group having 1 to 6 carbon atoms.
  • a methylthio group, an ethylthio group, a n-propylthio group, an i-propylthio group, a n-butylthio group, an i-butylthio group, a s-butylthio group and a t-butylthio group can be mentioned.
  • a methylthio group is more preferable.
  • the "C 1-6 alkylsulfonyl group” represents a straight or branched alkylsulfonyl group having 1 to 6 carbon atoms.
  • a methylsulfonyl group, a n-propylsulfonyl group, an i-butylsulfonyl group and a n-hexylsulfonyl group can be mentioned.
  • a methylsulfonyl group is more preferable.
  • the "C 2-9 heterocyclyl group” represents a 5 to 7-membered monocyclic heterocyclyl group or a fused polycyclic heterocyclyl group constituted of 10 to 14 atoms, constituted of at least one atom selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom and 2 to 9 carbon atoms.
  • a tetrahydrofuranyl group, a tetrahydropyranyl group, an isothiazolidinyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a 1,3-oxazolidinyl group, a 1,6-dihydropyridazinyl group, a thiazolidinyl group, an indolinyl group, a 1,6-dihydropyrimidinyl group, a 1,2,3,4-tetrahydropyrimidinyl group and a 4,5-dihydro-1,3-thiazol-2-yl group can be mentioned.
  • the "C 7-14 arylalkyl group” represents a straight or branched alkyl group having a total number of carbon atoms of 7 to 14 and having a monocyclic or polycyclic aromatic hydrocarbon group as a substituent or a group having a total number of carbon atoms of 7 to 14 and obtained by fusing a monocyclic or polycyclic aromatic hydrocarbon group with a straight or branched alkyl group.
  • a benzyl group, a phenethyl group, a phenylpropyl group, a naphthylmethyl group, an indanyl group, a (2H)-indenyl group and a tetrahydronaphthyl group can be mentioned.
  • a benzyl group and a phenethyl group are more preferable.
  • the "C 1-9 heteroaryl group” represents a 5 to 7-membered monocyclic aromatic heterocyclyl group constituted of at least one atom selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom and 1 to 9 carbon atoms, or a fused polycyclic aromatic heterocyclyl group constituted of 10 to 14 atoms.
  • a pyrazolyl group, a thiazolyl group, a triazolyl group, a pyridyl group, an isoxazolyl group, a pyrazinyl group and a thiadiazolyl group are more preferable.
  • the "carboxy C 1-6 alkyl group” represents a "C 1-6 alkyl group” having a carboxy group as a substituent.
  • a carboxymethyl group, a 2-carboxyethyl group, a 3-carboxy-n-propyl group, a 2-carboxy-n-propyl group, a 2-carboxy-i-propyl group and a 4-carboxy-n-butyl group can be mentioned.
  • a carboxymethyl group is more preferable.
  • the "C 2-6 alkoxycarbonyl C 1-6 alkyl group” represents a "C 1-6 alkyl group” having a "C 2-6 alkoxycarbonyl group” as a substituent.
  • a methoxycarbonylmethyl group, a 2-(methoxycarbonyl)ethyl group, a 3-(methoxycarbonyl)-n-propyl group, a 2-(methoxycarbonyl)-n-propyl group, a 2-(methoxycarbonyl)-i-propyl group, an ethoxycarbonylmethyl group and a 2-(ethoxycarbonyl)ethyl group can be mentioned.
  • An ethoxycarbonylmethyl group is more preferable.
  • the "carbamoyl C 1-6 alkyl group” represents a "C 1-6 alkyl group” having a carbamoyl group as a substituent.
  • a carbamoylmethyl group for example, a carbamoylmethyl group, a 2-carbamoylethyl group, a 3-carbamoyl-n-propyl group, a 2-carbamoyl-n-propyl group, a 2-carbamoyl-i-propyl group and a 4-carbamoyl-n-butyl group can be mentioned.
  • a carbamoylmethyl group is more preferable.
  • the "di(C 1-6 alkyl) amino group” represents an amino group having two "C 1-6 alkyl groups" which may be the same or different, as a substituent.
  • a dimethylamino group, a diethylamino group, a di-n-propylamino group, a di-i-propylamino group, a di-i-butylamino group, a di-s-butylamino group, a di-t-butylamino group, an ethyl(methyl)amino group and a methyl(n-propyl)amino group can be mentioned.
  • the "di(C 1-6 alkyl) amino C 1-8 alkyl group” represents a "C 1-8 alkyl group” having a "di(C 1-6 alkyl)amino group" as a substituent.
  • a (dimethylamino)methyl group, a 2-(dimethylamino)ethyl group, a 2- ⁇ di(n-propyl)amino ⁇ ethyl group, a di(i-propyl)aminomethyl group, a 2-(ethylmethylamino)ethyl group and a 2- ⁇ (methyl)-(n-propyl)amino ⁇ ethyl group can be mentioned.
  • a 2-(dimethylamino)ethyl group is more preferable.
  • the monocyclic or fused polycyclic C 1-9 heteroaryl group represented by the formula (2) represents a 5 to 7-membered monocyclic aromatic heterocyclyl group constituted of at least one atom selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom and 1 to 9 carbon atoms, or a fused polycyclic aromatic heterocyclyl group constituted of 10 to 14 atoms, in which a nitrogen atom of the amide group positioned next to this group in the formula (1) is bonded to a carbon atom forming the following bond in this group.
  • a pyrazolyl group, a thiazolyl group, a pyridyl group, a pyrazinyl group, a thiadiazolyl group, a pyridothiazolyl group, an isoxazolyl group and an oxazolyl group can be mentioned.
  • the monocyclic C 1-6 heteroaryl group represented by formula (2) represents a 5 to 7-membered monocyclic aromatic heterocyclyl group constituted of at least one atom selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom and 1 to 6 carbon atoms, in which a nitrogen atom of the amide group positioned next to this group in the formula (1) is bonded to a carbon atom forming the following bond in this group.
  • a pyrazolyl group, a thiazolyl group, a pyridyl group, a pyrazinyl group, a thiadiazolyl group, an isoxazolyl group and an oxazolyl group can be mentioned.
  • the C 2-9 heterocyclyl group represented by formula (2) represents a 5 to 7-membered monocyclic heterocyclyl group constituted of at least one atom selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom and 2 to 9 carbon atoms or a fused polycyclic aromatic heterocyclyl group formed of 10 to 14 atoms, in which a nitrogen atom of the amide group positioned next to this group in the formula (1) is bonded to a carbon atom forming the following bond in this group.
  • a 4,5-dihydro-1,3-thiazol-2-yl group is more preferable.
  • a pharmaceutically acceptable salt is, for example, a mineral acid salt such as a hydrochloride, a hydrobromide, a hydroiodide, a phosphate, a sulfate and a nitrate; a sulfonate such as methane sulfonate, ethane sulfonate, benzene sulfonate and p-toluene sulfonate; a carboxylate such as an oxalate, a tartrate, a citrate, a maleate, a succinate, an acetate, a benzoate, a mandelate, an ascorbate, a lactate, a gluconate and a palate; an amino acid salt such as a glycine salt, a lysine salt, an arginine salt, an ornithine salt, a glutamic acid salt and an aspartic acid salt; or an inorganic salt such
  • a hydrochloride, a, hydrobromide, a phosphate, a sulfate, a methane sulfonate, a p-toluene sulfonate, an oxalate, a tartrate, a citrate, an acetate, a lactate, a glutamic acid salt, an aspartic acid salt, a sodium salt, a potassium salt, an ammonium salt or a triethylamine salt is mentioned.
  • a solvate represents a pharmaceutically acceptable solvate of a compound of the present invention or a salt thereof.
  • a compound of the present invention and a salt thereof When a compound of the present invention and a salt thereof are exposed to the air or recrystallized, they may absorb moisture and turn into compounds with absorption water and hydrates.
  • the compound of the present invention includes such a hydrate.
  • Some of the compounds of the present invention have an asymmetric center. In this case, various types of optical isomers are present. Accordingly, a compound of the present invention can be present in the form of a (+) configuration (single substance), a (-) configuration (single substance), a racemic mixture thereof or a ( ⁇ ) mixture containing optically active substances of both configurations in an arbitrary ratio.
  • diastereomers derived from individual optical isomerism are also present.
  • a compound having all types of isomers in an arbitrary ratio is included in the compound of the present invention.
  • a diastereomer can be separated by a well-known method to one skilled in the art, for example, fractional crystallization.
  • an optically active substance can be obtained by a well known organic chemical method developed for this purpose.
  • some of the compounds of the present invention have geometric isomers such as a cis-isomer and a trans isomer.
  • a compound containing these isomers in an arbitrary ratio is also included in the compound of the present invention.
  • a pyrazinamide compound of the present invention may be a pharmaceutically acceptable salt thereof or a solvate of these.
  • a pyrazinamide compound of the present invention including a tautomer, a stereo isomer or a pharmaceutically acceptable salt thereof or a solvate thereof will be referred to as "the compound of the present invention”.
  • a compound generally called prodrug which have a group that can be chemically or metabolically decomposed and is capable of forming a pharmacologically active compound of the present invention by solvolysis or in vivo under physiological conditions are included in "the compound of the present invention”.
  • the compound of the present invention has a GK activation action. Therefore, the compound of the present invention enhances glucose metabolism and glycogen synthesis in the liver, glucose inductive insulin secretion from the pancreatic beta cell, thereby correcting elevated blood glucose.
  • the compound of the present invention can be used as a new drug that differs from a conventional therapeutic agent for diabetes in mechanism of action. Diabetes includes Type I diabetes, Type II diabetes and other types of diabetes caused by specific causes.
  • the compound of the present invention is effective also for treating and preventing diabetic complications such as ketoacidosis, microangiopathy (retinopathy, nephropathy), arteriosclerosis (atheroma arteriosclerosis symptom, myocardial infarction, cerebral infarction, peripheral artery confinement), neuropathy (of sensory nerves, motor nerves, autonomous nerve), foot gangrene and an infectious disease.
  • diabetic complications such as ketoacidosis, microangiopathy (retinopathy, nephropathy), arteriosclerosis (atheroma arteriosclerosis symptom, myocardial infarction, cerebral infarction, peripheral artery confinement), neuropathy (of sensory nerves, motor nerves, autonomous nerve), foot gangrene and an infectious disease.
  • the compound of the present invention can be used for treating and preventing diabetes-related disorders such as obesity, hyperlipemia, hypertension, metabolic syndrome, edema, hyperuricemia and gout.
  • the compound of the present invention can be used in combination with a therapeutic agent for diabetes, a therapeutic agent for diabetes complication, a therapeutic agent for hyperlipemia and a therapeutic agent for hypertension, etc. whose mechanism of action differs from that of the GK activation action. If the compound of the present invention is used in combination with other pharmaceutical(s), a synergistic effect, which is higher than the sum of the effects obtained by single agents on the aforementioned disorders, can be expected.
  • Examples of the therapeutic agents for diabetes and therapeutic agents for diabetes complications that can be used in combination include an insulin preparation, an insulin-resistance improving agent (PPAR ⁇ agonist, PPAR ⁇ / ⁇ agonist, PPAR ⁇ agonist, PPAR ⁇ / ⁇ / ⁇ agonist, etc.) (e.g., Pioglitazone, Rosiglitazone, GW-501516, GW-590735, ABT-335, AZD-6,610, AVE-8133), ⁇ -glucosidase inhibitor (e.g., Voglibose, Acarbose, Miglitol), a biguanide agent (e.g., Metformin, Buformin, Phenformin), an insulin secretion accelerator (e.g., Glibenclamide, Glimepiride, Repaglinide, Nateglinide, Mitiglinide), an insulin preparation, a glucagon receptor antagonist, an insulin receptor kinase accelerator, dipeptidyl-peptidase IV
  • Pramlintide a glucocorticoid receptor antagonist, a 11 beta HSD1 inhibitor (e.g., AMG-221, INCB-13739), a protein kinase C inhibitor (e.g., Ruboxistaurin), a Beta-3 adrenaline receptor agonist (e.g., AJ-9677), a phosphatidyl inositol kinase inhibitor, a phosphatidyl inositol phosphatase inhibitor, an ACC inhibitor, a GPR40 receptor agonist, a GPR119 receptor agonist (e.g., APD-668), TGR5 receptor agonist, an AMPS activating agent (e.g., DRL-16536), an aldose reductase inhibitor and an AGE inhibitor.
  • a 11 beta HSD1 inhibitor e.g., AMG-221, INCB-13739
  • a protein kinase C inhibitor e.g., Ruboxistaurin
  • Examples of pharmaceuticals for diabetes-related disorders that can be used in combination include a HMG-CoA reductase inhibitor, a squalene synthetase inhibitor, a bile acid adsorbent, an IBAT inhibitor, a CETP inhibitor, a CPT inhibitor, a vibrate pharmaceutical, an ACAT inhibitor, an MGAT inhibitor, a DRAT inhibitor, a cholesterol absorption inhibitor, a pancreatic lipase inhibitor, an MTP inhibitor, a nicotinic acid derivative, an LXR agonist, an LDL receptor accelerator, an angiotensin-converting enzyme inhibitor, an angiotensin II antagonist, a diuretic agent, a calcium antagonist, an endothelin-converting enzyme inhibitor, an endothelin receptor antagonist, an anorexigenic agent, a uric acid generation inhibitor and a uric acid excretion stimulator.
  • a HMG-CoA reductase inhibitor a squalene synthetase
  • the compound of the present invention can be administered singly or in combination with a pharmaceutically or pharmacologically acceptable carrier or diluent.
  • a pharmaceutically or pharmacologically acceptable carrier or diluent When the compound of the present invention is used as a GK activating substance or the like, the compound of the present invention may be directly administered orally or parenterally.
  • an agent containing the compound of the present invention as an active ingredient may be administered orally or parenterally.
  • parenteral administration include an intravenous administration, transnasal administration, transdermal administration, subcutaneous administration, intramuscular administration and sublingual administration.
  • the dose of the compound of the present invention varies depending upon an administration target, an administration route, a subject disorder and a symptom, etc.
  • one dose when it is orally administered to an adult diabetic patient, one dose is usually about 0.01 to 100 mg/kg weight, preferably 0.05 to 30 mg/kg weight and further preferably 0.1 to 10 mg/kg weight. This dose is desirably administered once to three times per day.
  • the compound of the present invention can be synthesized by the process shown below; however, the following production process is an example of a general production process and will not limit the production process.
  • Step (1-1) a when Y is -O- or -S-, a compound (1-a) and a compound represented by the formula R 1 -Y-H are reacted in a solvent in the presence of a base such as potassium carbonate or sodium hydride to successfully produce a compound (1-b).
  • a base such as potassium carbonate or sodium hydride
  • Y is -NH-
  • a compound (1-a) is reacted with a compound represented by the formula R 1 -NH 2 , which is also serves as a solvent, to successfully produce a compound (1-b).
  • a condensing agent such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or 1-hydroxybenzotriazole
  • a base such as triethylamine or diisopropylethylamine
  • a C 2-6 alkoxycarbonyl group is present in the Ar moiety, it is hydrolyzed by use of a base such as an aqueous sodium hydroxide solution to be successfully converted into a carboxy group.
  • a C 1-6 alkoxy group is present in the R 1 moiety, it is reacted by use of a Lewis acid such as boron tribromide to be successfully converted into a hydroxy group.
  • Step (1-5) in a solvent, the compound (1-b) is hydrolyzed by use of a base such as an aqueous sodium hydroxide solution to successfully produce a compound (1-f).
  • R 1 and Ar are the same as defined above; and D is a group represented by the following formula ( ⁇ ) : (the formula ( ⁇ ) represents a C 2-9 heterocyclyl group or a C 1-9 heteroaryl group)).
  • the compound (2-c) is reacted with a nitrite compound such as t-butyl nitrite in the absence of an acid and subsequently reacted with a brominating agent such as copper (II) bromide to successfully produce compound (2-d).
  • Step (2-5) in a solvent, the compound (2-e) is hydrolyzed by use of a base such as an aqueous sodium hydroxide solution to successfully produce a compound (2-f).
  • a condensing agent such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or 1-hydroxybenzotriazole in the presence or absence of a base such as triethylamine or diisopropylethylamine to successfully produce the compound of the present invention (2-g).
  • Step (3-1) in a solvent, the compound (2-c) is hydrolyzed by use of a base such as an aqueous sodium hydroxide solution to successfully produce a compound (3-a).
  • a base such as an aqueous sodium hydroxide solution
  • a condensing agent such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or 1-hydroxybenzotriazole
  • a base such as triethylamine or diisopropylethylamine
  • Step (4-1) in a solvent, the compound (4-a) is hydrolyzed by use of a base such as an aqueous sodium hydroxide solution to successfully produce a compound (4-b).
  • a base such as an aqueous sodium hydroxide solution
  • a condensing agent such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or 1-hydroxybenzotriazole
  • a base such as triethylamine or diisopropylethylamine
  • Step (4-3) in a solvent, the compound (4-c) and a compound represented by the formula R 2 -Z-H are reacted in the presence of a base such as potassium carbonate by use of a palladium reagent such as tris(dibenzylideneacetone)palladium and a phosphine ligand such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene to successfully produce the compound of the present invention (4-d).
  • a base such as potassium carbonate
  • a palladium reagent such as tris(dibenzylideneacetone)palladium
  • a phosphine ligand such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
  • Step (5-1) in a solvent, a compound (5-a), a phosphine reagent such as triphenylphosphine or tributylphosphine and an azo reagent such as diethylazodicarboxylate or diisopropylazodicarboxylate are reacted and subsequently, the Mitsunobu reaction is carried out by use of a compound represented by the formula R 1 -OH to successfully produce a compound (5-b).
  • a phosphine reagent such as triphenylphosphine or tributylphosphine
  • an azo reagent such as diethylazodicarboxylate or diisopropylazodicarboxylate
  • a condensing agent such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or 1-hydroxybenzotriazole
  • a base such as trieth
  • a general production process for a pharmaceutically acceptable salt of the compound of the present invention is as follows. In the case of a compound forming an acid addition salt, the compound is dissolved in an appropriate solvent and mixed with an acid such as hydrochloric acid and oxalic acid directly or in a dissolved state. The resultant precipitate or a precipitate obtained by adding a poor solvent is obtained by filtration as a desired product. In this manner, the corresponding acid addition salt can be produced.
  • a compound of the present invention forming a base addition salt
  • the compound is dissolved in an appropriate solvent and mixed with a base such as sodium hydroxide, potassium hydroxide and arginine directly or in a dissolved state.
  • a base such as sodium hydroxide, potassium hydroxide and arginine directly or in a dissolved state.
  • the resultant precipitate or a precipitate obtained by adding a poor solvent is obtained by filtration as a desired product. In this manner, the corresponding base addition salt can be produced.
  • alkali metal salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, sodium hydride, lithium hydride, sodium amide, potassium t-butoxide, n-butyl lithium and lithium diisopropylamide, amines such as triethylamine, diisopropylethylamine, pyrrolidine and piperidine, sodium acetate, and potassium acetate
  • the solvent according to a general process for producing the compound of the present invention is not particularly limited as long as it is stable and labile in the reaction conditions and it does not inhibit the reaction.
  • reaction temperature As the reaction temperature according a general process for producing the compound of the present invention, an appropriate temperature can be selected within the range from -78°C to a boiling point of the solvent to be used in the reaction.
  • the production process of the present invention can be performed under normal pressure, under pressure and irradiation of microwave etc.
  • reaction mixture was charged with t-butyl nitrite (11.4 ml, 86.0 mmol) and was further stirred for 30 minutes at an external temperature of 50°C.
  • the resultant low polarity product was washed with hexane-ethyl acetate to obtain 3-bromo-6-iodopyrazine-2-carboxylic acid methyl ester (6.38 g) in the form of a white solid substance.
  • a high-polarity product was washed with ethyl acetate to obtain 3-hydoxy-6-iodopyrazine-2-carboxylic acid methyl ester (2.70 g) in the form of a yellow solid substance.
  • GK activation action of the compound of the present invention was measured by the method described in the following experimental example.
  • a GK activation by a test compound was tested by partially modifying the method of Irwin A. Rose et al. (J. Biol. Chem. 1964 Jan; 239: 12-7 ).
  • the enzyme source used in this assay was human liver GK, which was allowed to express by Escherichia coli as a fusion protein having GST (Glutathione S-transferase) added to the amino terminal and purified by Glutathione Sepharose 4B (Amersham Biosciences).
  • the test was performed by using flat-bottom 96-well plates (Sumitomo Bakelite Co., Ltd).
  • a dimethyl sulfoxide (DMSO) solution of a test compound and DMSO serving as a control were added so as to obtain a final DMSO concentration of 1%.
  • 25 mM Hepes-KOH (pH 7.1)
  • 25 mM KCl, 2 mM MgCl 2 , 2 mM ATP, 4 mM 14 C-labeled glucose (Amersham Pharmacia) and 1 mM DTT (dithiothreitol) (these concentrations were final concentrations) were added.
  • human liver GK was added so as to obtain 0.24 ⁇ g/well. The reaction was initiated and carried out at room temperature.
  • the GK activity activated by the test compound to a maximum was indicated as the maximum activation value (Emax value). Furthermore, the concentration of a test compound required for activating GK activity to 50% of the maximum activation value was indicated as an EC 50 value. The results are shown in Table 2 below.
  • the effect of the compound of the present invention to decrease blood glucose level was investigated by use of SD rats.
  • SD rats were raised by free-feeding. From the caudal vein of 8-week old mice, blood was taken and centrifugally separated to obtain the plasma. A blood glucose level of the plasma was measured by glucose CII test Wako.
  • the rats were divided into groups of 6 rats so as to have the same average blood glucose level. In an agent administration group, a compound suspended in a 0.5% aqueous methyl cellulose solution was orally administered to the rats; whereas, in a control group, a 0.5% aqueous methylcellulose solution was orally administered.
  • the plasma was centrifugally recovered and a blood glucose level was measured by use of glucose CII test Wako. Furthermore, a plasma insulin concentration was measured by an ultrasensitive rat insulin measuring kit (Morinaga Institute of Biological Science, Inc.). The blood glucose levels at individual time points were plotted to obtain a graph showing a change of blood glucose level. Regarding the blood glucose level of the 0.5% methyl cellulose administration group as 100%, the blood glucose level of SD rats administrated with Compound No. 2 was indicated.
  • the blood glucose level was 59% at 1 hour, 71% at 2 hours and 76% at 4 hours.
  • the blood glucose level was 53% at 1 hour, 68% at 2 hours, and 75% at 4 hours.
  • Granules containing the following components are manufactured.
  • Components Compound represented by the formula (1) 10 mg Lactose 700 mg Cornstarch 274 mg HPC-L 16 mg 1000 mg
  • a compound represented by the formula (1) and lactose are passed through a 60-mesh sieve.
  • Cornstarch is passed through a 120 mesh sieve.
  • These are mixed by a V-shape mixer.
  • a low-viscosity aqueous hydroxypropyl cellulose (HPC-L) solution is added, kneaded, granulated (extruding granulation, pore size: 0.5 to 1 mm) and then dried.
  • the resultant dried granules are passed through a shaking sieve (12/60 mesh) to obtain granules.
  • Component Compound represented by the formula (1) 10 mg Lactose 79 mg Cornstarch 10 mg Magnesium stearate 1 mg 100 mg
  • a compound represented by the formula (1) and lactose are passed through a 60-mesh sieve. Cornstarch is passed through a 120 mesh sieve. These and magnesium stearate are mixed by a V-shape mixer. Then, 10 triturated powder (100 mg) is encapsulated in a No. 5 hard gelatin capsule.
  • Component Compound represented by the formula (1) 15 mg Lactose 90 mg Cornstarch 42 mg HPC-L 3 mg 150 mg
  • a compound represented by the formula (1) and lactose are passed through a 60-mesh sieve.
  • Cornstarch is passed through a 120 mesh sieve. These are mixed by a V-shape mixer.
  • a low-viscosity aqueous hydroxypropyl cellulose (HPC-L) solution is added, kneaded, granulated and then dried.
  • the resultant dried granules are passed through a shaking sieve (12/60 mesh) to obtain granules.
  • the granules 150 mg
  • Tablets containing the following components are manufactured.
  • Component Compound represented by the formula (1) 10 mg Lactose 90 mg Microcrystalline cellulose 30 mg Magnesium stearate 5 mg CMC-Na 15 mg 150 mg
  • a compound represented by the formula (1), lactose, microcrystalline cellulose and CMC-Na (sodium salt of carboxymethylcellulose) were passed through a 60-mesh sieve and mixed.
  • magnesium stearate is added to obtain powder mixture for a preparation.
  • the powder mixture was directly tableted to obtain 150 mg tablets.
  • a preparation for intravenous administration is manufactured as follows.
  • Compound represented by the formula (1) 100 mg Saturated fatty acid glyceride 1000 ml
  • a solution containing the above components is intravenously administered to a patient generally at a rate of 1 ml/minute.
  • the compound of the present invention has excellent GK activation action and can provide therapeutic and prophylactic agents not only for diabetes but also for diabetes-related disorders such as obesity and hyperlipemia or for diabetic chronic complications such as retinopathy, nephropathy and arteriosclerosis.

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US20100190980A1 (en) 2010-07-29
WO2008156174A1 (ja) 2008-12-24

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